This proposal's long-term objective is to develop a mechanism-based therapeutic drug for the treatment ofhuman acute myeloid leukemias (AML), which are among the deadliest cancers in the United States. Despitesome advances in treatment, survival for AML has not improved significantly in decades, with rare exceptionsfor specific subclasses. While targeted therapies with FLT3, IDH, and Bcl-2 inhibitors have increased responserates significantly, survival has been extended only by several months. Thus, novel and innovative therapeuticdrugs are needed to improve the survival outcomes of AML patients. The sphingolipid ceramide, an emergingtumor suppressor lipid, mediates anti-proliferative signaling events in response to various stress stimuli,including tyrosine kinase inhibitors (TKIs). Our published and unpublished data suggest that decreased levelsof C18-ceramide might be critical in the pathophysiology, progression and drug-resistance of AML. These dataalso revealed that reconstitution of C18-ceramide by molecular and pharmacologic tools results in thesuppression of AML growth, and help overcome drug resistance. Because of pharmacologic challenges of theconventional exogenous short-chain ceramides, we have developed novel mitochondrial targeted pyridinium-C18-ceramide (Pyr-Cer) analogs that induce cancer cell mitophagy and tumor suppression. These Pyr-Ceranalogs exhibit increased water solubility, cell-membrane permeability, and cancer cell-selective mitochondrialuptake, compared to uncharged conventional ceramides. Pyr-Cer analog drugs, such as LCL461 (patentedClass I) or LCL768 (Class II), contain a positive charge at a delocalized pi-electron system. This then results inpreferential localization of the drug into highly negatively charged mitochondria in cancer cells/tissues due tothe Warburg effect. The accumulation of Pyr-Cer in mitochondria results in cancer cell death via induction ofmitophagy by reducing cellular energy generation and decreasing the synthesis of other vital macromolecules,such as nucleotides. This effect of Pyr-Cer on mitophagy induction is further increased when cancer cells areexposed to general ROS/RNS inducer sodium selenite that causes Drp1 activation and mitochondrial fission.Thus, we have generated a new (Class II) Pyr-Cer analog drugs conjugated with sodium selenite, named asSoSe-C18-Pyr-Cer (LCL768), which selectively induced mitophagy-dependent cell death in AML in situ and invivo. Based on these data, our goal is to develop LCL768 as an anti-cancer drug for the treatment of AML. Inthese feasibility studies, we will: 1) Validate the mechanism by which Pyr-Cer drugs target AML mitochondriaby mitophagy in vitro; and 2) Determine bioactivity, toxicity, pharmacokinetics and anti-AML activity of LCL768in vivo. We will determine the possible off-target effects, maximum tolerated dose (MTD),pharmacokinetic/pharmacodynamic profiles and anti-AML effects of LCL768 in various models. These includedrug sensitive versus resistant AML xenografts, AML PDXs, and primary AML blasts. This Phase I feasibilitystudy will help the commercial development of LCL768 for a Phase II application.
Public Health Relevance Statement: NARRATIVE
The main objective of this proposal is to develop a mechanism-based therapeutic drug for the treatment of
human acute myeloid leukemia (AML) via reconstitution of tumor suppressive C18-ceramide using Class I and
Class II novel pyridinium-ceramide (Pyr-Cer) analogue drugs, such as LCL461 and LCL768, which selectively
induce mitophagy-dependent cell death in AML.
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